title: Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress.
abstract: Glucagon-like peptide 1 (GLP-1) is a growth factor that has demonstrated neuroprotective properties in a range of studies. In an APPswe/PS1ΔE9 mouse model of Alzheimer's disease (AD), we previously found protective effects on memory formation, synaptic plasticity, synapse survival and a reduction of amyloid synthesis and plaque load in the brain. Here, we analyse the neuroprotective properties of the GLP-1 analogue liraglutide in human neuroblastoma cell line SH-SY5Y during methyl glyoxal stress. We show for the first time that cell viability was enhanced by liraglutide (XTT assay) in a dose-dependent way, while cytotoxicity (LDH assay) and apoptosis were reduced. Expression of the pro-survival Mcl1 signaling protein was increased, as was activation of cell survival kinases Akt, MEK1/2 and the transcription factor p90RSK. Liraglutide also decreased pro-apoptotic Bax and Bik expression. In addition, the membrane potential and the influx of calcium into the cell were enhanced by liraglutide. GLP-1 receptor expression was also increased by the drug. The results demonstrate a range of growth factor-related cytoprotective processes induced by liraglutide, which is currently on the market as a treatment for type 2 diabetes (Victoza®). It is also tested in clinical trials in patients with Alzheimer disease.
authors.affiliation: Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.
authors.forename: Mohit K
authors.initials: MK
authors.lastname: Sharma
authors.forename: Jaishree
authors.initials: J
authors.lastname: Jalewa
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D000069450:Liraglutide; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018696:Neuroprotective Agents; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011765:Pyruvaldehyde / Q000633:toxicity*; D018027:Receptors, Glucagon / Q000096:biosynthesis / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D018027:Receptors, Glucagon; D051028:bcl-2-Associated X Protein; D011765:Pyruvaldehyde; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D002118:Calcium
keywords: Alzheimer's disease; apoptosis; incretins; insulin; neurodegeneration; neuroprotection